The complement (C) system of humans and other mammals involves more than 20 components that participate in an orderly sequence of reactions resulting in complement activation. The blood complement system has a wide array of functions associated with a broad spectrum of host defense mechanisms including anti-microbial and anti-viral actions (Muller-Eberhard (1988) Annu. Rev. Biochem. 57:321-347; Rother et al. (1984) in Contemporary Topics in Immunology, Vol. 14 (Snyderman, R., Ed.), pp. 109-153, Plenum Publishing Company, New York). Products derived from the activation of C components include non-self recognition molecules C3b, C4b and C5b, as well as the anaphylatoxins C3a, C4a and C5a that influence a variety of cellular immune responses (Hugli et al. (1982) 15th International Leucocyte Culture Conference, Asilomar, Calif. (Abstract); Fujii et al. (1993) Protein Science 2:1301-1312; Morgan et al. (1982) J. Exp. Med. 155:1412-1426; Morgan (1993) Complement Today 1:56-75; Morgan et al. (1983) J. Immunol. 130:1257-1261). These anaphylatoxins also act as pro-inflammatory agents (Chenoweth et al. (1983) Agents Actions 12:252-273; Hugli et al. (1978) in Advances in Immunology, Dixon et al., Eds., pp. 1-53, Academic Press, New York). The role of C in The C system also has a role in immuno-pathogenesis of a number of disorders, including autoimmune diseases such as rheumatoid arthritis (see, e.g., Wang et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92:8955-8959; Moxley et al. (1987) Arthritis & Rheumatism 30:1097-1104), lupus erythematosus (Wang et al. (1996) Proc. Natl. Acad. Sci. U.S.A. 93:8563-8568; and Buyon et al. (1992) Arthritis Rheum. 35:1028-1037) and acute glomerulonephritis (Couser et al. (1995) J. Am. Soc. Nephrol. 5:1888-1894). Other pathologies that involve activation of the C system include sepsis (see, e.g., Stove et al. (1996) Clin. Diag. Lab. Immunol. 3:175-183; Hack etal. (1989) Am. J. Med. 86:20-26), respiratory distress syndrome (see, e.g., Zilow et al. (1990) Clin. Exp. Immunol. 79:151-157; and Stevens et al. (1986) J. Clin. Invest. 77:1812-1816) and multiorgan failure (see, e.g., Hecke et al. (1997) Shock 7:74; and Heideman etal. (1984) J. Trauma 241038-1043). Interest in such pathologies as well as interest in C-activation associated with transplanted organ rejection (see, e.g., Dalmasso et al. (1992) Immunopharmacology 24:149-160; Kirschfink et al. (1992) Transplantation Proceedings 24: 2556-2557) reveals a need for a reliable and accurate assay system for monitoring in vivo C-activation in patient populations.
The complement system is made up of an array of enzymes and non-enzymatic proteins and receptors. The enzymes include a group of seven serine proteases: factor D, C1r, C1s, MASP, factor B, C2 and factor I. Complement activation occurs by one of three primary modes known as the "classical" pathway, the "alternative" pathway and the lectin pathway (see e.g., Ember et al. (1997) Immunopharmacology 38:3-15).
These pathways are distinguished by the processes that initiate complement activation. The classical pathway is initiated by antibody-antigen complexes or aggregated forms of immunoglobulins; the alternative pathway is initiated by several ways, including spontaneous cleavage of a thioester, by certain structures on microbial and cell surfaces, such as amino groups, hydroxyl groups, and by water, and the lectin pathway, which is an antibody-independent pathway that is initiated by the binding of mannan-binding lectin (MBL, also designated mannan-binding protein) to carbohydrates (see, e.g., Thiel et al. (1997) Nature 386:506-510).